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Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [ 14 C]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD. [ABSTRACT FROM AUTHOR]

People living in Africa face a heavy and wide-ranging burden of disease that takes an incalculable toll on social and economic development as well as shortening life expectancy (life expectancy in Tanzania is about 60 vs. about 80 in the United States and Europe. Further, the pharmaceutical market in developing countries is immature and may not support quality medicines. In many cases, a tender system is used, and medicines are bought by the government at the lowest price. In addition to access to medicines, a number of pharmaceutical sciences problems are apparent. The availability of infrastructure and especially standard instruments such as HPLC and X-ray diffraction is minimal. Additionally, there is an important need to increase access to advanced education for men and women in Africa, especially access to state-of-the-art scientific education. Utilizing the mandate of Nelson Mandela, Purdue's conceptual approach has been to utilize education to combat these problems. [ABSTRACT FROM AUTHOR]

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions—coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified. [ABSTRACT FROM AUTHOR]

Pathophysiological changes are associated with alterations in the expression and function of numerous ADME-related proteins. We have previously demonstrated that the membrane localization of ATP-binding cassette ( ABC) transporters in liver was decreased without change of total expression levels in adjuvant-induced arthritis ( AA) in rats. Ezrin/radixin/moesin ( ERM) proteins are involved in localization of some ABC transporters in canalicular membrane. The m RNA levels of radixin decreased significantly in liver but not kidney, small intestine, and brain. The m RNA levels of ezrin and moesin did not change in AA. The membrane localization of radixin was reduced in liver of AA and the ratios of activated radixin (p-radixin) to total radixin were decreased in AA, although the protein levels of radixin did not change in homogenate and membrane protein. To clarify whether AA affects the linker functions of ERM proteins, we examined the interactions between ERM proteins and ABC transporters. The interactions between radixin and ABC transporters were decreased in AA. In vitro studies using human hepatoma Hep G2 cells showed that interleukin-1β decreased the m RNA levels of radixin and colocalization of radixin and Mrp2. Our results show that the decreased radixin functions affect the interaction between radixin and ABC transporters in inflammation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4058-4065, 2014 [ABSTRACT FROM AUTHOR]

Ensuring the health of street-involved children is a growing public health challenge. These children are vulnerable, neglected, and rarely a priority for basic service providers and governments. Sizable populations of street-involved children are present in major urban areas worldwide and current trends in urbanization suggest these populations will grow in the coming years. Although migration offers employment and training opportunities, the health and wellbeing of children is negatively impacted by their interactions with the streets. However, systemic barriers may also prevent these children from achieving an adequate health status. The situation of street-involved children in Ghana, West Africa will be discussed. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3619-3622, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low K m enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated. [Copyright &y& Elsevier]

Most of the global healthcare issues facing us—from expanding access to care, to providing medical and dental care in the aftermath of disasters—are far too complex for any single sector to successfully solve. Industry, the healthcare profession, government, academia and non-governmental organizations (NGOs) are all limited in their scope and their ability to effectively address the necessary challenges of these multifaceted issues. It is only though public–private partnerships, in which the participants contribute resources and skills for which they individually are best suited, that true progress can be made in affecting change. In addition, every effort should be made to expand the pool of participants for these partnerships, including small and mid-sized organizations that may be inclined to help, but lack the experience or the infrastructure to initiate programs on their own. As the largest distributor of healthcare products and services to office-based practitioners in the combined North American and European markets, Henry Schein, Inc., is uniquely positioned to use its association with thousands of healthcare product manufacturers and its day-to-day relationships with more than 550,000 healthcare practices around the world to catalyze awareness of and support for important healthcare issues. Through Henry Schein's model for giving, the Company has been successful in forging new partnerships among industry, the healthcare profession, government, academia and NGOs, and in expanding existing ones to help meet the healthcare challenges facing us all. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5084–5088, 2008 [ABSTRACT FROM AUTHOR]

Dehydroepiandrosterone sulfate (DHEAS) is a 19-carbon steroid, situated along the steroid metabolic pathway. It is the most abundant circulating steroid hormone in the body and can be converted to either androgens or estrogens. Their physiological and pathological functions have not yet been fully identified. Serum DHEAS concentrations peak at around age 25 years and then decline steadily over the following decades. Due to its long half-life and high concentration in the blood, the levels of DHEAS remain the same 24 h a day. This makes DHEAS a very interesting new diagnostic tool for both scientific research and clinical diagnostics. Moreover, circulating concentrations of DHEAS can be changed by many factors, such as endogenous production, hormone supplementation, many kinds of drugs, and many types of disease states. As research moves forward to better understand the relationships of DHEAS with health and disease, it is essential that studies should be designed to control for the influence of many factors on serum DHEAS concentrations. [Copyright &y& Elsevier]

• Selected organofluorine-containing blockbuster drugs were profiled. • General aspects of the biological properties of these compounds were briefly introduced. • The synthetic methods for preparation of these organofluorine-containing drugs were presented. The role of organo-fluorine compounds in modern health, food and energy related industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasingly being used in the development of new bioactivities. Around 25 % of the current blockbuster drugs contain fluorine and this number is increasing to well above 30 % for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action. [ABSTRACT FROM AUTHOR]